rs121912433

Positions:

• chr21-31663841-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000454.5(SOD1):​c.124G>A​(p.Gly42Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SOD1 NM_000454.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.01

Genes affected

SOD1 (HGNC:11179): (superoxide dismutase 1) The protein encoded by this gene binds copper and zinc ions and is one of two isozymes responsible for destroying free superoxide radicals in the body. The encoded isozyme is a soluble cytoplasmic protein, acting as a homodimer to convert naturally-occuring but harmful superoxide radicals to molecular oxygen and hydrogen peroxide. The other isozyme is a mitochondrial protein. In addition, this protein contains an antimicrobial peptide that displays antibacterial, antifungal, and anti-MRSA activity against E. coli, E. faecalis, S. aureus, S. aureus MRSA LPV+, S. agalactiae, and yeast C. krusei. Mutations in this gene have been implicated as causes of familial amyotrophic lateral sclerosis. Rare transcript variants have been reported for this gene. [provided by RefSeq, Jul 2020]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a strand (size 9) in uniprot entity SODC_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000454.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 21-31663841-G-A is Pathogenic according to our data. Variant chr21-31663841-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 14754.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SOD1	NM_000454.5	c.124G>A	p.Gly42Ser	missense_variant	2/5	ENST00000270142.11	NP_000445.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SOD1	ENST00000270142.11	c.124G>A	p.Gly42Ser	missense_variant	2/5	1	NM_000454.5	ENSP00000270142	P1
SOD1	ENST00000389995.4	c.67G>A	p.Gly23Ser	missense_variant	2/5	3		ENSP00000374645
SOD1	ENST00000470944.1	n.1052G>A		non_coding_transcript_exon_variant	2/5	2
SOD1	ENST00000476106.5	n.387G>A		non_coding_transcript_exon_variant	3/5	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251496 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135922

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Amyotrophic lateral sclerosis type 1 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 04, 1993	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 20, 2022	This variant disrupts the p.Gly42 amino acid residue in SOD1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8446170, 9029070, 16291929, 16793335, 26069299, 28291249). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects SOD1 function (PMID: 19483195, 20404329). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SOD1 protein function. ClinVar contains an entry for this variant (Variation ID: 14754). This variant is also known as Gly41Ser. This missense change has been observed in individuals with autosomal dominant amyotrophic lateral sclerosis (PMID: 8446170, 19488901, 21755517). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs121912433, gnomAD 0.0009%). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 42 of the SOD1 protein (p.Gly42Ser). -

Amyotrophic lateral sclerosis type 1;C5231422:Spastic tetraplegia and axial hypotonia, progressive Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 07, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D;.
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Pathogenic	3.3	M;.
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-5.6	D;D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0080	D;D
Sift4G	Uncertain	0.022	D;D
Polyphen		1.0	D;.
Vest4		0.85
MutPred		0.91		Gain of disorder (P = 0.1645);.;
MVP		1.0
MPC		2.3
ClinPred		0.99	D
GERP RS		4.9
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.8
Varity_R		0.88
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs121912433; hg19: chr21-33036154;